Synthesis and biological evaluation of N-heterocyclic carbene–silver(I) acetate complexes derived from 4,5-ditolyl-imidazole

Abstract

From the reaction of 1,2-bis-(4-methylphenyl)ethane-1,2-dione with formamide, symmetrically substituted 4,5-bis-(4-methylphenyl)-1H-imidazole (1) was synthesised and further reacted with p-benzyl substituted halides to give the symmetrically substituted N-heterocyclic carbene (NHC) precursors 1a–e.The NHC precursors were then reacted with silver(I) acetate to yield NHC–silver(I) acetate complexes 1,3-bis-(benzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2a), 1,3-bis-(4-methylbenzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2b), 1,3-bis-(4-methoxylbenzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2c), 1,3-bis-(4-methoxycarbonylbenzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2d) and 1,3-bis-(4-cyanobenzyl)-4,5-bis-(4-methylphenyl)-imidazole-2-ylidene silver(I) acetate (2e).Two NHC–silver acetate complexes 2a and 2e were characterised by single crystal X-ray diffraction. The preliminary in vitro antibacterial activity of the NHC–silver complexes 2a–e was investigated against Gram-positive bacteria Staphylococcus aureus and Gram-negative bacteria Escherichia coli using the qualitative Kirby–Bauer disk-diffusion method. The areas of clearance determined for the maximum dose (4.3μM) range between 1mm and 7mm for MSSA and 0mm and 7mm for E. coli. All of the newly synthesised silver(I) acetate complexes were tested for their cytotoxicity by MTT based in vitro tests on the human renal cancer cell line Caki-1 and human breast cancer cell line MCF-7 in order to determine their IC50 values.The NHC–silver complexes 2a–e were found to have IC50 values of 3.0 (±0.6), 0.51 (±0.07), 4.2 (±1.2), 9.0 (±0.6), 26 (±2)μM, against the renal cancer cell-line Caki-1 and IC50 values of 2.3 (±0.4), 1.4 (±0.2), 3.0 (±0.5), 3.4 (±1.2) and 14 (±2)μM against the breast cancer cell line MCF-7, respectively. Compared to our lead compound SBC3 (1,3-bisbenzyl-4,5-bisphenyl-imidazole-2-ylium silver(I) acetate) (IC50 value=14 (±1)μM against Caki-1 and 5.8 (±0.6)μM against MCF-7) these values represent improved cytotoxicity against both cell lines, especially for the silver complexes 2a and 2b. These two compounds are not only more active than SBC3 but also exhibit in the case of 2b a 7 times higher biological activity than cisplatin (IC50 value=3.3μM) against Caki-1.